Abstract Asthma is a major health problem worldwide whose prevalence has reached epidemic proportions and that exacts a heavy toll of morbidity. The high prevalence of asthma over the last decades reflects the interaction of susceptibility genes in affected individuals with environmental and life style changes ushered by the industrial revolution. A hallmark of asthma is chronic inflammation and tissue remodeling. Concerted efforts have gone into characterizing the asthmatic inflammatory response and establishing the underlying mechanisms that drive and sustain it long-term. Asthma, a heterogeneous disorder in its phenotypic manifestations, encompasses several disease endotypes, or underlying pathophysiologic mechanisms. Relevant to this proposal is a mixed TH2/TH17 endotype characterized by mixed eosinophilic and neutrophilic inflammation in the airways and is associated with more difficult to treat and steroid-resistant asthma. We have recently shown that an interleukin 4 receptor (IL-4R) variant associated with severe asthma, IL-4R?-R576, uniquely drives mixed TH2/TH17 cell inflammation in the airways, tightly segregating with asthmatics with this endotype. We have further determined that the mechanism by which this variant promotes mixed TH2/TH17 inflammation involves IL-4-dependent subversion of allergen-specific induced regulatory T (iTreg) cells into a TH17 cell-like phenotype, leading to their degeneration into bona fide allergen-specific pathogenic TH17 cells. The IL-4R?-R576 is associated with severe and difficult to treat asthma, and is particularly common among inner city pediatric age asthmatics. We established dose response relationships with IL-17 in comparing the wild type (Q576/Q576), heterozygous mutant (Q576/R576), and homozygous (R576/R576) mutant alleles and asthma morbidity. These observations provide the rationale to use IL-4R blockade with the anti-IL-4R monoclonal antibody (mAb) Dupilumab with the dual purpose of interrupting the IL-4-dependent mixed TH2/TH17 cell inflammation and simultaneously restoring tolerance. This proposal brings together investigators with deep expertise in allergic diseases, genetics and tolerance to address the hypothesis that pediatric age asthmatics harboring this variant will manifest a particular favorable response to Dupilumab and that the IL-4R?-R576 variant drives mixed TH2/TH17 cell inflammation in the airways by subverting allergen-specific induced T regulatory (iTreg) cell responses into the TH17 cell lineage. We will also explore the potential of long-term tolerance. To investigate this overarching hypothesis this trial and mechanistic studies are led by investigators recognized for their expertise and with a proven track record of collaboration with each other. We will examine the clinical response of these children to therapy based on genotype and examine the evolution of the T cell inflammatory and regulatory responses in asthmatic children stratified by their IL-4R genotype treated with either placebo or Dupilumab. These investigations promise precision medicine-guided effective therapy directed by the IL-4R?-R576 genotype that specifically targets a disease-driving endotype in children with difficult to treat asthma.